The rewiring of cAMP/cGMP and LDH signalling drives cardiac hypertrophy in Pde5a-/- mice

Phosphodiesterase type 5a (Pde5a), an enzyme that hydrolyzes cGMP nucleotide, regulates several aspects of heart physiology and its inhibition improves left ventricular heart function under pathological conditions. We investigated Pde5a role in the development and progression of moderate and severe cardiac hypertrophy, induced by transverse aortic constriction (TAC), in Pde5a WT (Pde5a+/+) and Pde5a-deficient (Pde5a−/−) mice. Cardiac hypertrophy was surprisingly detected in Pde5a−/− mice after TAC surgery with similar alterations of cardiac function, morphology, fibrosis, and expression of molecular markers compared with Pde5a+/+ mice. The Pde5a inhibitor, Sildenafil, prevented only moderate cardiac hypertrophy at the morphofunctional and molecular levels in Pde5a+/+ mice. Cardiac hypertrophy was found to be associated with unbalanced cAMP/ cGMP ratio and lactate dehydrogenase plays a critical role in the metabolic remodelling of Pde5a−/− hearts under TAC conditions. In conclusion, pharmacological Pde5a inhibition counteracts moderate but not severe hypertrophy. Genetic ablation of Pde5a does not protect against moderate/severe cardiac hypertrophy. In the absence of Pde5a, the oxidative metabolism shifts towards a mixed oxidative-glycolytic metabolism under TAC condition.